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Nicola Gökbuget

Publications and source records attributed to Nicola Gökbuget.

At least 19 recordsLinked to original sources
PubMed2006

Molecular relapse in adult standard-risk ALL patients detected by prospective MRD monitoring during and after maintenance treatment: data from the GMALL 06/99 and 07/03 trials.

Although levels of minimal residual disease (MRD) decrease below the detection limit in most adult patients with standard-risk acute lymphoblastic leukemia (ALL) after consolidation treatment, about 30% of these patients will ultimately relapse. To evaluate the power of MRD monitoring as an indicator of impending relapse, we prospectively analyzed postconsolidation samples of 105 patients enrolled in the German Multicenter ALL (GMALL) trial by real-time quantitative polymerase chain reaction (PCR) of clonal immune gene rearrangements. All patients were in hematologic remission, had completed first-year polychemotherapy, and tested MRD negative prior to study entry. Twenty-eight of 105 patients (27%) converted to MRD positivity thereafter, and 17 of 28 (61%) relapsed so far. Median time from molecular (MRD-positive) to clinical relapse was 9.5 months. In 15 of these patients, MRD within the quantitative range of PCR was measured in hematologic remission, and 13 of these patients (89%) relapsed after a median interval of 4.1 months. Of the 77 continuously MRD-negative patients, only 5 (6%) have relapsed. We conclude that conversion to MRD positivity during the early postconsolidation phase in adult standard-risk ALL patients is highly predictive of subsequent hematologic relapse. As a result of the study, as of spring 2006, salvage treatment in the ongoing GMALL trial is intended to be started at the time of recurrence of quantifiable MRD.

Adolescent↗
PubMed2006

High expression of the ETS transcription factor ERG predicts adverse outcome in acute T-lymphoblastic leukemia in adults.

PURPOSE: In adult T-lymphoblastic leukemia (T-ALL) disease-free survival remains limited to 32% to 46%. The adverse prognosis in T-ALL has not been attributed to cytogenetic or molecular aberrations. We have determined the prognostic impact of the oncogenic transcription factor ERG in T-ALL. PATIENTS AND METHODS: ERG expression was analyzed by real-time polymerase chain reaction (PCR) in 105 adults with newly diagnosed T-ALL treated on the German ALL protocols. Patients were dichotomized at ERG's median expression into low (n = 52) and high (n = 53) expressers. Homeobox (HOX) 11 and HOX11L2 expression was determined by real-time PCR. RESULTS: High ERG expressers compared with low ERG expressers had an inferior overall survival (OS, P = .02; 5-year OS: high ERG 26% v low ERG 58%) and relapse-free survival (RFS, P = .003; 5-year RFS: high ERG 34% v low ERG 72%). On multivariable analysis high ERG expression (P = .005), immunophenotypic subgroups (early v mature v thymic T-ALL; overall P = .04), HOX11L2 positivity (P = .055), and absence of HOX11 (P = .017) were independent adverse risk factors predicting RFS. Patients with high ERG expression had a hazard ratio (HR) for relapse of 3.2. Within the good prognostic subgroup of thymic T-ALL (n = 57), high ERG (HR, 4.1; P = .02) and presence of HOX11L2 (HR, 6.6; P = .008) were independent adverse factors for RFS. CONCLUSION: High expression of ERG is an adverse risk factor in adult T-ALL. Within thymic T-ALL, otherwise classified as standard-risk, high ERG expression-identified patients that were four times more likely to fail long-term RFS. The prognostic impact of ERG may assist treatment stratification and suggest the need of alternative regimens.

Adolescent↗
PubMed2006

NUP214-ABL1 in adult T-ALL: the GMALL study group experience.

The NUP214-ABL1 fusion gene in T-cell acute lymphoblastic leukemia (T-ALL) has recently been identified as a possible target for imatinib and related tyrosine kinase inhibitors, but exact data regarding the prognostic impact and frequency of the several putative NUP214-ABL1 mRNA transcripts are still missing. We investigated 279 adult patients with T-ALL treated within the framework of the GMALL 5/93 and 6/99 therapy trials for NUP214-ABL1 by using a novel multiplex real-time, quantitative polymerase chain reaction (PCR). Eleven (3.9%) patients were NUP214-ABL1 positive, and 5 different transcripts were observed; 8 patients had a thymic immunophenotype, 1 had an early T-cell immunophenotype, and 2 had a mature T-cell immunophenotype. NUP214-ABL1-positive and -negative patients did not differ significantly in their major clinical features. In contrast to previous reports suggesting an adverse clinical course for NUP214-ABL1-positive patients, no significant difference in overall survival was observed. Based on the results, we have established and tested a novel PCR method for simplified detection of the NUP214-ABL1 fusion gene.

Adolescent↗
PubMed2006

[Clinical research within the German competence net "acute and chronic leukemias"].

BACKGROUND: Leukemias are a challenge and a cost factor to society because of their frequency in all age groups. They also serve as a model for a variety of diseases and possess exemplary relevance for basic research and patient care. Leukemia research and therapy have achieved high standards and even a leading position in Germany with regard to clinical trials, standardization of diagnostics and molecular studies of prognostic factors, signal transduction and gene expression. Progress is hampered, however, by fragmentation of leukemia trial groups, diagnostic approaches and treatment research activities. GOALS: A network was therefore created to integrate the leading leukemia trial groups on chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphatic leukemia (ALL), myelodysplastic syndromes (MDS) and chronic myeloproliferative diseases (CMPD) and their interdisciplinary partners (diagnostics, treatment research, biometry) in cooperation with basic research and pharmaceutical industry to foster advancements in leukemiarelated research and health care through clinical trials, promotion of translational research, introduction of standards for diagnostics and therapy, and development of evidence-based guidelines. ACHIEVEMENTS: Achievements include establishment of central information, communication and management structures, creation of an AML intergroup comprising five study groups, formation of an MDS study group and establishment of platforms for diagnostics, genomics and proteomics, and medical informatics. Exchange of scientific progress is mediated by intra- and internet, biannual newsletters, regular project group meetings, and annual network symposia. PERSPECTIVES: On the basis of experience with the Competence Network "Acute and chronic leukemias" with its management, communication and information structures, the "European LeukemiaNet" (ELN) has been established within the 6th Framework Program of the European Union. The ELN integrates 78 leading leukemia trial groups (AML, ALL, CML, CLL, MDS, and CMPD), their 83 interdisciplinary partner groups (diagnostics, treatment research, registry, guidelines), industry and SMEs (small- and medium-sized enterprises) across Europe to form a cooperative network for advancements in leukemia-related research and health care.

Acute Disease↗
PubMed2006

Novel antibody-based therapy for acute lymphoblastic leukaemia.

In recent decades rapid improvements in the results of treatment of adult acute lymphoblastic leukaemia (ALL) have been achieved. This progress has been based mainly on intensification and optimization of chemotherapy, risk-adapted use of stem-cell transplantation, and improved supportive care. However, results in adult patients are still considerably inferior to those in paediatric ALL, and a barrier to further intensification of chemotherapy appears to have been reached regarding toxicity. More recently, the most significant progress has therefore been achieved by individualized and targeted therapy - for example, treatment with monoclonal antibodies (MoAbs). ALL blast cells express a variety of specific antigens which may serve as targets: e.g. CD19, CD20, CD22, CD33, and CD52. Most experience is available for anti-CD20 (rituximab). In ALL, rituximab is combined with chemotherapy mainly in mature B-ALL and Burkitt's lymphoma, and interim results are very promising. Recently studies with rituximab have also been initiated in B-precursor ALL. Other antibodies would be of interest due to a high rate of antigen (e.g. CD19) expression in ALL, but these are not yet generally available. Clinical application in smaller studies or case reports was reported for anti-CD52 and anti-CD33. Overall it can be stated that MoAb therapy in ALL is a promising treatment approach. Monotherapy with MoAbs in relapsed ALL has also occasionally achieved responses, but greater effects can be expected from combination with chemotherapy and treatment in the state of minimal residual disease. Details of these regimens - required level of antigen expression, timing, schedule, dosage and stage of disease - remain to be defined.

Antibodies, Monoclonal↗
PubMed2006

Treatment of adult acute lymphoblastic leukemia.

In the early 1980s, adult acute lymphoblastic leukemia (ALL) was a rarely curable disease with overall survival < 10%. After adapting combinations employed by pediatric groups, the outcome improved to 30-40%. A period of stagnation followed with improvement only in distinct subgroups. In the past 5 years, however, striking new developments have been noticeable. Progress has been made in molecular diagnostics of ALL. Improvements to standard therapy including stem cell transplantation (SCT) have occurred and a variety of new drugs for ALL are under evaluation. Rapid diagnosis and classification of ALL is increasingly important to identify prognostic factors and molecular genetic subsets that will be the focus of "targeted" therapies as we enter the era of subset specific treatment. In the following review we will discuss treatment of adult ALL (excluding elderly patients,(1) adolescents(2) and patients with Ph/BCR-ABL positive ALL(3)).

Adult↗
PubMed2005

Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia.

Adult patients with acute lymphoblastic leukemia (ALL) who are stratified into the standard-risk (SR) group due to the absence of adverse prognostic factors relapse in 40% to 55% of the cases. To identify complementary markers suitable for further treatment stratification in SR ALL, we evaluated the predictive value of minimal residual disease (MRD) and prospectively monitored MRD in 196 strictly defined SR ALL patients at up to 9 time points in the first year of treatment by quantitative polymerase chain reaction (PCR). Frequency of MRD positivity decreased from 88% during early induction to 13% at week 52. MRD was predictive for relapse at various follow-up time points. Combined MRD information from different time points allowed definition of 3 risk groups (P < .001): 10% of patients with a rapid MRD decline to lower than 10(-4) or below detection limit at day 11 and day 24 were classified as low risk and had a 3-year relapse rate (RR) of 0%. A subset of 23% with an MRD of 10(-4) or higher until week 16 formed the high-risk group, with a 3-year RR of 94% (95% confidence interval [CI] 83%-100%). The remaining patients whose RR was 47% (31%-63%) represented the intermediate-risk group. Thus, MRD quantification during treatment identified prognostic subgroups within the otherwise homogeneous SR ALL population who may benefit from individualized treatment.

Adolescent↗
PubMed2003

Treatment with monoclonal antibodies in acute lymphoblastic leukemia: current knowledge and future prospects.

After rapid improvement of treatment results in adult acute lymphoblastic leukemia (ALL) from less than 10% to 30-40% in the past decades, more recently stagnation has been observed. In addition, a borderline for further intensification of chemotherapy appears to be reached in adult ALL patients. New, preferably non-chemotherapy, approaches are therefore urgently required. One of those is targeted therapy with monoclonal antibodies (MoAbs). ALL blast cells express a variety of specific antigens which may serve as targets, such as CD19, CD20, CD22, CD33, and CD52. Published results of MoAbs in ALL are reviewed. Most experience is available for anti-CD20 (rituximab) which led to a significant improvement of the outcome in B-cell non-Hodgkin's lymphoma (NHL). In ALL, rituximab is combined with chemotherapy mainly in mature B-ALL and Burkitt's lymphoma and preliminary results are promising. In the future, studies will also be done in B-precursor ALL. Another promising B-cell antibody is anti-CD22. Several CD19 MoAbs were also tested in phase I studies. However, results are not conclusive and these MoAbs are not generally available. Far less experience with MoAb therapy is available for T-ALL, but clinical studies are on the way with anti-CD52 and anti-CD25 in adult T-cell leukemia/lymphoma. Overall, it can be stated that MoAb therapy in ALL is a promising treatment approach. Monotherapy with MoAbs in relapsed ALL occasionally led to responses, but higher effectivity can be expected from a combination with chemotherapy and treatment in the state of minimal residual disease. Well-designed studies and joint efforts are required to explore optimal combinations, timing and dosage of MoAb therapy in ALL.

Antibodies, Monoclonal↗
PubMed2003

Early prediction of response in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) treated with imatinib.

Imatinib has pronounced but brief antileukemic activity in advanced Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL). We assessed the prognostic impact of pretreatment disease features and the early bone marrow (BM) response in 68 consecutive patients with Ph(+)ALL receiving imatinib salvage therapy. A complete hematologic or marrow response was achieved by 92% of patients with BM blasts below 5% on day 14, whereas 62.5% of patients with more than 5% BM blasts on day 14 were nonresponders. Similarly, time to progression (TTP) was superior in patients with a good day 14 response (5.2 versus 0.9 months; P <.0001). Prior complete remission of less than 6 months, white blood cell count of more than 10 x 10(9)/L, circulating peripheral blood blasts at diagnosis, additional Philadelphia chromosomes, or at least 2 Bcr-Abl fusion signals were associated with significantly inferior remission rate and response duration. In patients without poor prognostic features, single-agent imatinib may be appropriate before transplant salvage therapy. Conversely, patients with clinically or cytogenetically defined poor-risk features are candidates for trials of upfront imatinib in combination with other agents.

Adolescent↗
PubMed2003

Risk and prognosis of central nervous system leukemia in patients with Philadelphia chromosome-positive acute leukemias treated with imatinib mesylate.

PURPOSE: In patients with acute leukemias, a lymphoid phenotype, the presence of a Philadelphia chromosome (Ph), and inadequate central nervous system (CNS)-directed prophylactic therapy are risk factors for CNS involvement. Imatinib mesylate has promising single-agent antileukemic activity in patients with advanced Ph(+) acute leukemias. It was the aim of this analysis to determine the incidence of, and risk factors associated with, meningeal leukemia during imatinib monotherapy. STUDY DESIGN: We analyzed 107 consecutive patients with relapsed or refractory Ph(+) acute lymphoid leukemia (ALL; n = 65) or chronic myeloid leukemia blast crisis (n = 42) who were enrolled in successive Phase II trials of single-agent imatinib and who did not receive routine prophylactic intrathecal chemotherapy. RESULTS: CNS leukemia developed in 13 of 107 patients (12%) and was associated primarily with a lymphoid or bilineage phenotype (12 of 78; 15%) and with imatinib refractory Ph(+) ALL (5 of 19; 26%). Meningeal leukemia did not occur among patients who received prior prophylactic cranial irradiation. The median survival with combined CNS and systemic disease was 108 days (range, 58-141), with no patient surviving long term. In contrast, two of three patients with exclusively meningeal leukemia achieved prolonged molecular remissions with intrathecal chemotherapy, cranial irradiation, and continued imatinib. CONCLUSIONS: Patients with Ph(+) ALL are at considerable risk of meningeal leukemia during imatinib monotherapy and should routinely receive CNS prophylaxis. Although the prognosis with combined meningeal and systemic relapse is dismal, patients with an isolated meningeal relapse may still achieve sustained remissions. The optimal type of CNS-directed treatment and the extent of protection afforded by prophylactic cranial irradiation remain to be defined.

Adolescent↗
PubMed2002

Outcome of adult patients with T-lymphoblastic lymphoma treated according to protocols for acute lymphoblastic leukemia.

We treated 45 adult patients with T-lymphoblastic lymphoma (T-LBL) (age range 15-61 years) with 2 protocols designed for adult acute lymphoblastic leukemia (ALL). An encouraging cure rate of 90% was recently reported for T-LBL in children treated with a similar approach. In our study, an 8-drug standard induction was administered over 8 weeks including prophylactic cranial (24 Gy) and mediastinal irradiation (24 Gy) followed by consolidation and reinduction therapy. At diagnosis, 91% of the 45 patients showed a mediastinal tumor and 40% had pleural/pericardial effusions; 73% of the patients had stage III/IV disease. Overall, 42 patients (93%) achieved a complete remission (CR), 2 patients (4%) achieved a partial remission, and 1 patient (2%) died during induction. In patients with stage I-III disease (n = 18) the CR rate was 100% compared with 89% in stage IV (n = 27). There were 15 patients who relapsed (36%) within 12 months. The majority of relapses (47%) occurred in the mediastinum (n = 7) despite mediastinal irradiation with 24 Gy in 6 out of 7 patients. The estimates for overall survival, continuous CR, and disease-free survival at 7 years are 51%, 65%, and 62%, respectively. Stage, age, lactate dehydrogenase, and all other parameters had no influence on achievement of CR or outcome. This study demonstrates in a large cohort of patients with adult T-LBL that a high CR rate and a favorable outcome can be achieved with an ALL-type regimen. Mediastinal recurrence was the major obstacle and further improvement by intensification of chemotherapy, increased dose of mediastinal irradiation (36 Gy), and extended indications for stem cell transplantation seem to be required.

Adolescent↗
PubMed2002

Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis.

The BCR-ABL fusion, the molecular equivalent of the Philadelphia translocation, gains importance for treatment stratification in adult acute lymphoblastic leukemia (ALL). In this prospective study, samples from 478 patients with CD10(+) B-cell precursor ALL (c-ALL and pre-B ALL) underwent BCR-ABL reverse transcription-polymerase chain reaction (RT-PCR) analysis with double testing of positive samples. Patients were stratified according to the PCR result and treated in 2 German Multicenter Trials of Adult ALL. The outcome was followed and the prognostic impact of BCR-ABL was compared to clinical risk features. Of the 478 samples, 432 had an evaluable BCR-ABL result. Thirty-seven percent of the c-ALL and pre-B ALL patients were BCR-ABL(+) (p190, 77%; p210, 20%; simultaneous p190/p210, 3%). BCR-ABL positivity was associated with the high-risk features of older age (45 years versus 30 years median age; P =.0001) and higher white blood cell counts (23 500/microL versus 11 550/microL; P =.0001). Univariate and multivariate analyses revealed BCR-ABL as the leading factor for a poor prognosis (P =.0001) in comparison to clinical risk criteria. Irrespective of the breakpoint, presence of any BCR-ABL transcript predicted a lower chance of initial treatment response (68.4% versus 84.6%; P =.001) and a lower probability of disease-free survival at 3 years (0.13 versus 0.47; P =.0001). This bad outcome was not influenced by postinduction high-dose treatment stratifications. The results show a high prevalence of BCR-ABL fusion transcripts with predominance of p190. BCR-ABL RT-PCR is confirmed as a sensitive, rapid method to diagnose t(9;22), and p190 and p210 are unequivocally demonstrated as the most important predictors of poor long-term survival despite intensified chemotherapy.

Adolescent↗
PubMed2002

Recent approaches in acute lymphoblastic leukemia in adults.

In the last decades outcome of adult acute lymphoblastic leukemia (ALL) has improved considerably. In large multicenter studies remission rates range from 75% to 89%, and long-term leukemia-free survival (LFS) from 28% to 39%. Major progress has also been made regarding better characterization of subtypes of ALL. Complete diagnostic procedures are essential to identify these subtypes which have significant differences in clinical and laboratory features and prognosis. LFS of > 50% can be expected in favorable subtypes such as T-ALL or mature B-ALL, while LFS of < 20% is expected in Ph/BCR-ABL positive ALL. Prognostic factors can be used for risk stratification and selection of treatment strategies can be adapted to the subtype and relapse risk. This includes measurement of minimal residual disease (MRD) to evaluate individualized treatment strategies adapted to the molecular response. Several new approaches for improvement in chemotherapy and stem cell transplantation (SCT) are under investigation. They include the use of intensified anthracyclines, asparaginase, cyclophosphamide or high-dose cytarabine during induction and intensive rotational chemotherapy during consolidation. Also SCT - mainly from sibling donors - is now part of standard treatment of de novo ALL, although it remains open whether indications should be based on prognostic factors or whether SCT should be offered to all patients with sibling donor. However, substantial progress can only be achieved by new, experimental strategies. These include new approaches for SCT, such as nonmyeloablative SCT, measurement of MRD, causal treatment with molecular targeting, e.g. with kinase inhibitors, and antibody therapy.

Adult↗
PubMed2002

Risk-adapted treatment according to minimal residual disease in adult ALL.

The evaluation of minimal residual disease (MRD) is a new diagnostic method which is applicable in various malignant disorders. Acute lymphoblastic leukaemia (ALL) is a somewhat ideal disease in this respect because >90% of the patients show individual clonal markers and because several methods for MRD evaluation are already established. Futhermore, it was demonstrated that level and course of MRD are significantly correlated with relapse risk in childhood and in adult ALL. In clinical practice MRD evaluation may serve for several purposes such as follow-up of individual course of disease, identification of new prognostic factors or evaluation of single treatment elements. We discuss these options as well as general considerations for MRD-based risk stratification and treatment options for risk groups. Practical applications are analysed because prospective MRD-based clinical trials have been recently started. Finally, future options for application of MRD evaluation and also limitations and pitfalls of this method are reviewed.

Age Factors↗
PubMed2002

Treatment of lymphoblastic lymphoma in adults.

Lymphoblastic lymphoma (LBL) is a rare subtype of non-Hodgkin's lymphoma (NHL) with biological features similar to those of acute lymphoblastic leukaemia. In the majority of cases LBL shows a T-cell phenotype, and mediastinal tumours are the most frequent manifestation. Outcomes of LBL patients treated according to NHL or ALL-type regimens are reviewed. Since prophylaxis of CNS relapse and local recurrence emerged as important issues in the treatment of LBL the different options are discussed. Several studies have used autologous stem cell transplantation (SCT) in the primary treatment of LBL and results are reviewed. The analysis of published prognostic factors and models in LBL demonstrates that, at present, no convincing risk model is available for LBL treated according to contemporary intensive chemotherapy protocols. Therefore indications for SCT in first complete remission (CR) cannot be defined. Future prospects for improvement of treatment results in LBL include intensification of chemotherapy, definition of prognostic factors, evaluation of minimal residual disease and SCT in high-risk patients.

Adult↗